Department of Biochemistry and Molecular Biophysics - University of Pennsylvania Perelman School of Medicine

__________

Host:  Julien Roche

__________

"Protein Dynamics, Entropy and Function"

Molecular recognition by proteins is fundamental to the molecular basis of biology.  Dissection of the thermodynamic landscape governing protein-ligand interactions has proven difficult because determination of various entropic contributions is quite challenging.  NMR relaxation measurements, theory and simulations suggest that conformational entropy can be accessed through a dynamical proxy.  The construction and validation of a robust and relatively model independent relationship between measures of fast side chain motion and the underlying conformational entropy will be presented.

The dynamical proxy reveals that the contribution of conformational entropy can range from highly favorable to highly unfavorable and demonstrates the potential of this key thermodynamic variable to modulate protein-ligand interactions.  The dynamical “entropy meter” also refines the role of solvent entropy and directly determines the loss in rotational-translational entropy that occurs upon formation of high affinity complexes. 

Finally, preliminary data will be presented that suggests the purposeful manipulation of conformational entropy can be used to create a protein-protein complex with an unprecedented affinity.  Supported by the NIH and the G. Harold & Leila Y. Mathers Charitable Foundation.